Estradiol contained in follicular hormones is secreted from ovary when females are in a reproducible period. Therefore, females around the stage of perimenopause are deficient mostly in estradiol and suffer from climacteric changes and menopausal disorder. In order to improve those symptoms, a therapy by orally administering agents is carried out at present but, since they are quickly metabolized and inactivated by digestive organs such as stomach and intestine, liver, etc., it is necessary to take high doses of estradiol for expecting a sufficient expression of the pharmaceutical effect. In addition, there is a risk of an increase in expression of adverse actions and the like due to the high doses.
Under such circumstances, there has been attempts where a therapy is carried out in which estradiol is made to reach the blood by making its metabolism little by means of a percutaneous administration. On the other hand, there have been other attempts where another hormone—luteinizing hormone—is absorbed percutaneously whereby the adverse action in the administration of estradiol is suppressed. In Japanese Patent Laid-Open No. 342532/1992, there is proposed a percutaneously absorbing preparation mainly comprising estradiol and luteinizing hormone as pharmaceutical ingredients and an acrylate adhesive consisting of 2-ethylhexyl acrylate and N-vinyl-2-pyrrolidone as an adhesive. However, an acrylate adhesive has a low releasing ability of pharmaceuticals and has a strong irritation to skin and, therefore, it is hardly durable for a continuous administration during a long period.
In Japanese Patent Laid-Open No. 51623/1994, there is proposed a method where the pharmaceutical ingredients—estradiol and norethisterone acetate—are dissolved in a gel comprising hydroxypropyl cellulose and ethanol to make them into a reservoir type and release of the pharmaceutical ingredients is controlled using a permeability adjusting membrane. However, ethanol has a strong irritation to skin and there is a problem such as an adverse action causing a flare at the applied area in a high frequency. On the other hand, a percutaneous patch comprising a styrene-isoprene-styrene block copolymer using crotamiton as a solubilizer is proposed in International Patent Laid-Open WO 91/17752 and Japanese Patent Laid-Open No. 148145/1993. However, there is a problem in its stability that, when crotamiton is used as a solubilizer, the styrene-isoprene-styrene block copolymer itself is dissolved in crotamiton whereby the expected cohesive force is not achieved.
Hexylene glycol (generic name; its chemical name is 2-methyl-2,4-pentanediol) is usually used as moisturizer, solvent, cleaning agent in industry, hydraulic fluid, softener/softening agent for leather fiber, etc., agent for ink, agent for photography and the like. In Japanese Patent Laid-Open Nos. 109220/1995 and 53338/1996, there are proposed the agents for external use where hexylene glycol is used as an antibacterial agent. In International Patent Laid-Open WO 96/19976 and Japanese Patent Laid-Open No. 138153/1995, there are proposed the agents for external use where hexylene glycol is used as a sorbefacient. However, hexylene glycol has a high compatibility with acrylate bases and, in achieving a sufficient sorbefacient effect, it is necessary to compound hexylene glycol in a large amount. There is an additional problem of lowering of adhesive property and influence on the basic physical property of the preparation caused by compounding of a large quantity of hexylene glycol.
In view of the above problems, the present inventors have carried out an intensive investigation with an object of providing a percutaneous preparation or base in which
1) a high cutaneous permeation of pharmaceutical ingredients and
2) stabilization of physical property of the base are attempted and, as a result, the present invention has been accomplished.